Synergistic antitumor activity of METTL3 peptide degrader and immune checkpoint inhibitor in advanced urothelial cancer.

• DOI: 10.1200/jco.2024.42.16_suppl.e14623
• Publication Date: 2024-06-04T19:44:01Z
• Authors: Shihao Shang; Hong Han; Kepu Liu; Zenghui Li; Jie Zhang; Lei Zhang; Dongen Ju; Di Wei; Jianlin Yuan; Zheng Zhu; Junfeng Shi
• Keywords: Urothelial cancer

e14623 Background: In patients afflicted with advanced urothelial carcinoma (aUC), the durable response rate to immune checkpoint inhibitor (ICI) is approximately 20%. Recent study showed pivotal role of N6-methyladenosine (m6A) methyltransferase-like 3 (METTL3) in escape and progression aUC. This aimed develop a novel METTL3 peptide degrader RKL investigate its synergistic effects underlying mechanisms combination ICI for Methods: Methyltransferase expression profiles were scrutinized using The Cancer Genome Atlas database; while prognostic implications analyzed IMvigor210 cohort study. Single-cell RNA sequencing (scRNA-seq) was employed elucidate mechanistic insights. synthesized Fmoc solid-phase synthesis purified high-performance liquid chromatography. vivo vitro experiments conducted assess impact RKL, ICI, their on aUC inhibition. Results: aUC, exhibited most significant up-regulation among m6A methyltransferases, METTL14 WTAP down-regulated expression. study, elevated treated demonstrated poorer prognosis. scRNA-seq revealed that upregulation promoted genes regulating cancer-associated fibroblast proliferation, contributing enhanced tumor resistance immunotherapy. high toxicity cell lines, inhibiting proliferative, migratory, invasive capacities vitro. combined treatment significantly reduced volume (P<0.001), complete achieved 87.5% (7/8) mice group, 12.5% (1/8) 25.0% (2/8) group. Conclusions: overexpression associated therapy. when demonstrates antitumor warranting further exploration clinical research.